Endotheliopathy and Platelet Dysfunction as Hallmarks of Fatal Lassa Fever

Abstract

Lassa fever (LF) causes multisystem disease and has a fatality rate < 70%. Severe cases exhibit abnormal coagulation, endothelial barrier disruption, and dysfunctional platelet aggregation but the underlying mechanisms remain poorly understood. In Sierra Leone during 2015–2018, we assessed LF patients’ day-of-admission plasma samples for levels of proteins necessary for coagulation, fibrinolysis, and platelet function. P-selectin, soluble endothelial protein C receptor, soluble thrombomodulin, plasminogen activator inhibitor 1, ADAMTS-13, von Willebrand factor, tissue factor, soluble intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 were more elevated in LF patients than in controls. Endothelial protein C receptor, thrombomodulin, intercellular adhesion molecule 1, plasminogen activator inhibitor 1, D-dimer, and hepatocyte growth factor were higher in fatal than nonfatal LF cases. Platelet disaggregation occurred only in samples from fatal LF cases. The impaired homeostasis and platelet dysfunction implicate alterations in the protein C pathway, which might contribute to the loss of endothelial barrier function in fatal infections.

Bundibugyo ebolavirus Survival Is Associated with Early Activation of Adaptive Immunity and Reduced Myeloid-Derived Suppressor Cell Signaling

“…The thrombosis-associated markers PAI-1 and tissue plasminogen activator (tPA) were elevated in fatal macaques and survivors exhibiting severe illness after BDBV exposure, suggesting that these factors may also play a role in DIC. Higher PAI-1 levels were also found in pediatric patients infected with Sudan ebolavirus ( 36 ) and fatal human cases of Lassa virus disease ( 37 ), suggesting that this marker may represent a universal feature among hemorrhagic fever virus infections. PAI-1 is a serine protease inhibitor (serpin) that normally functions as an inhibitor of plasminogen activators like tPA and urokinase ( 38 ).…”

Lassa fever outcomes and prognostic factors in Nigeria (LASCOPE): a prospective cohort study

“…Thrombopenia was common and moderate. 20,21 These findings suggest that haemorrhaging might be driven by platelet dysfunction, 20,22 endothelial dysfunction, 22 and coagulopathy 21 rather than thrombocytopenia. We observed a high frequency of hypoalbuminaemia, which might be due to inflammation, digestive loss, renal loss, or vascular leakage.…”

Infection of Human Endothelial Cells with Lassa Virus Induces Early but Transient Activation and Low Type I IFN Response Compared to the Closely-Related Nonpathogenic Mopeia Virus

“…ECs are pivotal in the pathogenesis of viral hemorrhagic fevers, including LF. Indeed, although coagulopathy and thrombocytopenia contribute to the hemorrhagic signs and hypovolemic and hypotensive shock observed during severe LF [ 40 , 41 ], vascular leakage due to increased endothelial permeability also plays an important role in these events [ 26 ]. Increased EC permeability and the disruption of adherens junctions induced by Old and New World arenaviruses have been demonstrated in vitro [ 42 , 43 ] and their involvement in the pathogenic cascade confirmed in animal models of arenavirus diseases [ 44 , 45 , 46 ].…”

“…Only minor vascular lesions can be observed, in contrast to massive endothelial dysfunction [ 25 ]. ECs are activated by infection and diapedesis and release high amounts of intercellular adhesion molecule (ICAM), P-selectin, and the endothelial protein C receptor (EPCR) [ 26 ]. Platelet aggregation is also reduced, leading to the dysfunction of hemostasis.…”